Rona Yaeger, Meredith A McKean, Rizwan Haq, J Thaddeus Beck, Matthew H Taylor, Jonathan Eliezer Cohen, Daniel W Bowles, Shirish M Gadgeel, Catalin Mihalcioiu, Kyriakos P Papadopoulos, Eli L Diamond, Keren B Sturtz, Gang Feng, Stefanie K Drescher, Micaela B Reddy, Bhaswati Sengupta, Arnab K Maity, Suzy A Brown, Anurag Singh, Eric N Brown, Brian R Baer, Jim Wong, Tung-Chung Mou, Wen-I Wu, Dean R Kahn, Sunyana Gadal, Neal Rosen, John J Gaudino, Patrice A Lee, Dylan P Hartley, S Michael Rothenberg
RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling...
April 30, 2024: Cancer Discovery